title: Differential regulation of calcineurin isoforms in transplant patients: a new look at an old problem.
abstract: BACKGROUND
  Calcineurin is a ubiquitously expressed calcium-dependent phosphatase that is inhibited by the immunosuppressant drugs cyclosporine and tacrolimus. Measuring calcineurin activity in transplant patients has been complicated by a lack of consistent correlation between drug level and enzyme activity, particularly with chronic use. Data from mice lacking the CnAα or CnAβ isoform of the catalytic subunit of calcineurin demonstrate that loss of CnAβ results in immunosuppression, whereas loss of CnAα does not. As such, methods to examine activity of the CnAβ isoform may be more clinically relevant than nonspecific assays.
  
  
  METHODS
  Because the current enzyme assays are nonisoform specific, we examined association of the CnAα or CnAβ isoform with calmodulin (CaM), a shared binding protein that is only associated with the catalytic subunit in the presence of calcium. We then compared semiquantitated data with total calcineurin activity and immune status in a cohort of pretransplantation controls and postrenal transplantation patients.
  
  
  RESULTS
  We found no difference in calcineurin activity between the groups and no difference in the amount of non-isoform-specific catalytic subunit bound to CaM. However, association of CnAα-CaM is increased in transplant patients, whereas CnAβ-CaM is decreased. In addition, the amount of CnAβ-CaM corresponds positively with T-cell activity and negatively with tacrolimus level. Finally, CnAβ-CaM is lower in stable transplant patients compared with those with acute rejection.
  
  
  CONCLUSIONS
  These data suggest that monitoring specifically the β isoform may be more informative than non-isoform-specific assay methods.
authors.affiliation: Division of Nephrology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Pena
authors.forename: Lauren
authors.initials: L
authors.lastname: Titus
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jackson
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gooch
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008875:Middle Aged; D020033:Protein Isoforms
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D020033:Protein Isoforms; D019703:Calcineurin